Over 40,000 patients in the U.S. are diagnosed with head and neck cancers annually. Radiation therapy for these cancers causes irreparable damage to the salivary glands resulting in permanent xerostomia or dry mouth. Xerostomia significantly detracts from patient quality of life by adversely impacting oral hygiene, and currently no regenerative therapy exists to restore proper saliva secretion. Recent work has demonstrated that direct injection of primary submandibular gland (SMG) cells prepared by suspension culture into a radiation damaged glands leads to modest recovery of gland function in vivo. Thus, we aim to develop a biomaterials approach to augment gland recovery after irradiation by supporting SMG survival and function. Hydrogels, which are hydrophilic and bio-inert, have mechanical properties that are similar to those seen in soft tissues; however, few investigations have been reported regarding hydrogel-mediated salivary gland regeneration approaches. This project seeks to address this gap in knowledge by exploring the use of poly(ethylene glycol) (PEG) hydrogels as a means to transplant submandibular gland cells and regenerate functional salivary tissue. PEG hydrogels can be functionalized with both degradable and bioactive moieties to enhance the regenerative potential of SMG cells and can be formed in situ using photopolymerization. This project aims to develop permissive hydrogel encapsulation methods for primary salivary gland cells, design hydrogel milieus to promote salivary gland regeneration through cell-material interactions, and to form hydrogels in situ for salivary gland cell transplantation and gland regeneration. To design cytocompatible encapsulation methods, the effects of different types of hydrogel polymerizations on therapeutic SMG cells will be assessed in Aim 1. Cytocompatible PEG hydrogels chemistries will be further modified in Aim 2 to include cell-dictated degradability as well as vital cell adhesion motifs found in the salivary gland extracellular matrix (ECM) to improve the regenerative potential of the hydrogel scaffold. In Aim 3 SMG cells will be transplanted using in situ photopolymerization in both duct ligation and radiation models of salivary gland injury to track cell incorporation and functional gland recovery. Completion of these aims will determine the feasibility of hydrogel encapsulation for SMG based therapies and approach for tissue engineering approaches for the salivary gland. Detailed within this application are activities to complement the research training of the applicant. Both sponsors are dedicated to the applicant's development as a physician-scientist and will continue to train the applicant in experimental design, scientific writing, and presentation. The applicant will also pursue two longitudinal clinical experiences with physicians working in cancer treatment to gain a better understanding of the clinical context of his research. Finally, the applicant will continue involvement in the development of future studies during his medical training.